3-122282172-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM2PM5PP2BP4

The NM_000388.4(CASR):​c.1668G>T​(p.Glu556Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E556K) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0780
Variant links:
Genes affected
CASR (HGNC:1514): (calcium sensing receptor) The protein encoded by this gene is a plasma membrane G protein-coupled receptor that senses small changes in circulating calcium concentration. The encoded protein couples this information to intracellular signaling pathways that modify parathyroid hormone secretion or renal cation handling, and thus this protein plays an essential role in maintaining mineral ion homeostasis. Mutations in this gene are a cause of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a disulfide_bond (size 20) in uniprot entity CASR_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000388.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-122282170-G-A is described in Lovd as [Pathogenic].
PP2
Missense variant in the CASR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.1237 (above the threshold of 3.09). Trascript score misZ: 4.8257 (above the threshold of 3.09). GenCC associations: The gene is linked to epilepsy, autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 1, epilepsy, idiopathic generalized, susceptibility to, 8, neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1.
BP4
Computational evidence support a benign effect (MetaRNN=0.2867871).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CASRNM_000388.4 linkc.1668G>T p.Glu556Asp missense_variant Exon 6 of 7 ENST00000639785.2 NP_000379.3 P41180-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CASRENST00000639785.2 linkc.1668G>T p.Glu556Asp missense_variant Exon 6 of 7 1 NM_000388.4 ENSP00000491584.2 P41180-1
CASRENST00000498619.4 linkc.1698G>T p.Glu566Asp missense_variant Exon 6 of 7 1 ENSP00000420194.1 P41180-2
CASRENST00000638421.1 linkc.1668G>T p.Glu556Asp missense_variant Exon 6 of 7 5 ENSP00000492190.1 P41180-1
CASRENST00000490131.7 linkc.1437G>T p.Glu479Asp missense_variant Exon 4 of 5 5 ENSP00000418685.2 A0A1X7SBX3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152194
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461856
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152194
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Nephrolithiasis/nephrocalcinosis Uncertain:1
Feb 12, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.E556D variant (also known as c.1668G>T), located in coding exon 5 of the CASR gene, results from a G to T substitution at nucleotide position 1668. The glutamic acid at codon 556 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.0099
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.58
D;D;.;.
Eigen
Benign
-0.58
Eigen_PC
Benign
-0.47
FATHMM_MKL
Benign
0.72
D
LIST_S2
Uncertain
0.87
.;D;D;D
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.29
T;T;T;T
MetaSVM
Benign
-0.36
T
MutationAssessor
Benign
1.3
L;L;.;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-1.7
.;.;N;.
REVEL
Uncertain
0.33
Sift
Benign
0.16
.;.;T;.
Sift4G
Benign
0.14
.;.;T;.
Polyphen
0.0050
B;B;.;.
Vest4
0.15
MutPred
0.48
.;.;Gain of sheet (P = 0.0344);.;
MVP
0.79
MPC
0.57
ClinPred
0.33
T
GERP RS
-0.36
Varity_R
0.38
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs186279271; hg19: chr3-122001019; API